Microwave-assisted Claisen rearrangement of naphthyl 2-propynyl ethers: Synthesis of naphthofurans

Article abstract of DOI:10.1016/j.tetlet.2012.08.053

An efficient two-step approach for the synthesis of naphtho[1,2-b]furans and naphtho[2,1-b]furans has been developed. Various functionalized propargyl alcohols were etherified with α- or β-naphthol under Mitsunobu reaction conditions to give naphthyl 2-pr

Full text of DOI:10.1016/j.tetlet.2012.08.053

Tetrahedron Letters 53 (2012) 5695–5698
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Tetrahedron Letters
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Microwave-assisted Claisen rearrangement of naphthyl 2-propynyl ethers:
synthesis of naphthofurans
V. S. Prasada Rao Lingam a, Dnyaneshwar H. Dahale a, Kagga Mukkanti b, Balasubramanian Gopalan a,
Abraham Thomas a,
⇑
a Medicinal Chemistry Division, Glenmark Research Centre, Glenmark Pharmaceutical Ltd, MIDC, Mahape, Navi Mumbai 400 709, India
b Institute of Science and Technology, Jawaharlal Nehru Technological University Hyderabad, Hyderabad 500 072, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient two-step approach for the synthesis of naphtho[1,2-b]furans and naphtho[2,1-b]furans has
Received 12 July 2012
Revised 9 August 2012
Accepted 13 August 2012
Available online 19 August 2012
been developed. Various functionalized propargyl alcohols were etherified with a- or b-naphthol under
Mitsunobu reaction conditions to give naphthyl 2-propynyl ethers, which underwent a facile microwave-
assisted Claisen rearrangement and concomitant anionic cyclization to yield naphthofuran derivatives
under basic reaction conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Naphtho[1,2-b]furans
Naphtho[2,1-b]furans
Naphthyl 2-propynyl ethers
Claisen rearrangement
Cesium fluoride
Mitsunobu reaction
Microwave irradiation
The naphthofuran structural motif is found in several biologi-
cally active synthetic compounds and natural products.1 Napht-
hofuran-containing molecules are widely studied, for example, as
mediated cyclization of appropriate naphthoxy ketones prepared
from - or b-naphthol and
-halo ketone.12
a
a
Several other methods have also been reported for the synthesis
of naphthofuran derivatives such as reactions of tertiary
enaminoketones with p-naphthoquinones,13 Yb(OTf)3-catalyzed
conjugate addition of b-ketoesters to naphthoquinones,14 InCl3-
catalyzed propargylation of naphthols,15 PtCl2-catalyzed intramo-
lecular reaction of alkynes with furans,16 W(CO)5- catalyzed
electrocyclization of aromatic enynes,17 iron-catalyzed intramolec-
ular hydroaryloxylation of 2-propargyl naphthols,18 In(OTf)3-cata-
lyzed coupling between nitroalkenes and naphthols,19 copper
catalyzed cyclization of 3-(1-alkenyl)-2-alkene-1-al,20 intramolec-
hepatocyte nuclear factor 4 alpha (HNF4a
) inhibitors,2 nicotinic
acetylcholine receptor (nAChR) agonists,3 inhibitory kappa-b
kinase (IKKb) inhibitors,4 and nuclear transcription factor kappa-
b (NF-Kb) inhibitors.4 Naphthofuran derivatives are also reported
to possess diverse biological activities such as anti-diabetic,5
anti-inflammatory,6 antimicrobial,7 and analgesic activities.8 Natu-
ral products of particular significance with a naphthofuran nuclei
are furomollugin 19 and rubicordifolin 210 (Fig. 1) which have been
demonstrated to possess significant anticancer properties.1a
One of the most widely used approaches for the synthesis of
naphtho[2,1-b]furans of the general formula 4 involves the alkyl-
ular cyclization of
a
-styrylnaphthols,21 Pd(II)-catalyzed intramo-
lecular addition of arylboronic acids to ketones,22 gas-phase
pyrolysis of 2-allyloxy-1-naphthylpropenoic acid esters,23 reaction
ation of 1-acyl naphthols 3 with a-halo ketones or esters followed
by dehydrative cyclization of the acyl ether intermediate as shown
in Scheme 1.11 The same approach is also used for the preparation
of naphtho[1,2-b]furans using isomeric 2-acyl-1-naphthols.11 The
approach is generally more suitable for the synthesis of acyl or
acyloxy naphthofurans. A similar but less effective approach is also
reported for the synthesis of naphthofurans using neutral alumina
O
OCH3
O
OCH3
O
CH3
HO
HO
O
OH
H
O
O
HO
1
2
⇑
Corresponding author. Tel.: +91 22 6772 0000; fax: +91 22 2778 1206
E-mail address: abraham_thomas@glenmarkpharma.com (A. Thomas).
Figure 1. Structures of furomollugin 1 and rubicordifolin 2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.053

5696
V. S. Prasada Rao Lingam et al. / Tetrahedron Letters 53 (2012) 5695–5698
O
of b-naphthol 5 with appropriately functionalized propargyl alco-
hol 628 to give the desired Claisen substrate 7. Thus, the intermedi-
ate 7 was prepared by the reaction of 5 with propargyl alcohol 6 in
the presence of diethyl azodicarboxylate (DEAD) and triphenyl-
phosphine in dry tetrahydrofuran (THF) under Mitsunobu reaction
conditions.29 The reaction was found to be very general and ethers
7a–k30 were isolated in 90–96% yield.
R1
R
R
O
(i) BrCH2COR1
base
O
OH
(ii)
cyclization
3
4
Scheme 1. Literature synthesis of naphtho[2,1-b]furans.
To check the feasibility of Claisen rearrangement, 7a was sub-
jected to thermal rearrangement as reported in our previous pub-
lication.27 Thus, 7a was refluxed in N,N-diethylaniline (DEA) in the
presence of 1.5 equiv of cesium fluoride (CsF) for 36 h.31 The rear-
ranged product, 2-methyl-1-phenylnaphtho[2,1-b]furan 10a, was
isolated in poor 24% yield. Around 50% of unreacted alkyne ether
(7a) was also isolated from the mixture. As shown in Scheme 2,
7a underwent a [3,3]-sigmatropic rearrangement to the intermedi-
ate allenyl ketone 8 followed by enolization to 9 and 5-exo cycliza-
tion to the desired naphtho[2,1-b]furan 10a. Another experiment
under the same thermal conditions for 72 h resulted in nearly com-
plete disappearance of starting ether 7a. The desired product 10a
was isolated in 43% yield along with several unidentifiable prod-
ucts. The formation of 6-endo cyclization product 11 (1-aryl-3H-
benzo[f]chromene) was not observed in any of these reactions.31,32
The intermediate 7b bearing an electron rich aryl group and 7c
bearing an electron deficient aryl group were also subjected to
thermal rearrangement reaction. Both reactions were similar to
that of 7a and resulted in poor conversion (monitored by TLC) to
10b and 10c, respectively after prolonged (36 h) heating.
Ar
CH2
O
OH
Ar
CH2OH 6
DEAD, PPh3, THF
5
7a-k
CH2
CH2
C
Ar
C
Ar
MW
O
OH
CsF, DEA
8
Ar
9
CH3
O
Ar
cyclization
(5-exo)
O
10a-k
11
Scheme 2. Synthesis of naphtho[2,1-b]furans 10a–k.
We next explored the possibility of improving the yield of the
reaction under microwave irradiation.33 Heating a solution of 7a
in DEA in the presence of cesium fluoride in a sealed vessel
placed in a 200 W focused single-mode microwave reactor at
150 °C for 20 min resulted in complete consumption of starting
material and the product 10a34 was isolated in 85% yield. To
understand the scope of this reaction, a variety of substituents
were selected for microwave assisted Claisen rearrangement
(Table 1, entries 1–11). Aryl rings with both electron donating
(entry 2) and electron withdrawing groups (entries 3–5) gave
excellent yield in a very short reaction time. Even sterically
demanding ortho-substituted phenyl derivatives (entries 6,7)
resulted in an equally good yield. Substrates with aromatic het-
erocyclic rings such as 2-pyridine, 3-pyridine, 2-pyrazine, and
2-thiophene (entries 8–11) also resulted in good to excellent
yields demonstrating the generality and usefulness of the reac-
tion. The increase in yields of microwave-assisted reactions is
probably due to a shorter reaction time which in turn reduces
the number of possible side reactions.
of mono hydrazones of dicarbonyl compounds with 3,4-
dihydronaphthalen-1(2H)-one (tetralone),24 TiCl4 assisted rear-
rangement of allyl naphthyl ethers,25 and acid-catalyzed
rearrangement of cyclobutanones.26 However, most of these meth-
ods lack generality and involve multistep reactions from commer-
cially available starting materials.
We had previously reported base-assisted thermal Claisen rear-
rangement of various phenyl propargyl ethers and demonstrated
the use of this reaction for the synthesis of benzofuran deriva-
tives.27 In continuation of this work, we explored the scope of this
approach for the synthesis of naphthofurans. In this Letter, we re-
port the results of our study on microwave assisted Claisen rear-
rangement of naphthyl 2-propynyl ethers. We have also carried
out a few thermal rearrangement reactions for comparison and
to evaluate the strengths and pitfalls of the present approach.
As delineated in Scheme 2, the Claisen rearrangement strategy
for the synthesis of naphtho[2,1-b]furans 10 requires etherification
Table 1
Synthesis of naphtho[2,1-b]furans 10a–k34 and naphtho[1,2-b]furans 16a–d36
Entry
Ar
Ether
Yielda (%)
Naphthofuran
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5
7a
7b
7c
7d
7e
7f
7g
7h
7i
96
95
92
96
94
93
92
93
92
90
94
95
96
95
91
10a
10b
10c
10d
10e
10f
10g
10h
10i
20
25
15
15
15
25
25
25
20
20
45
25
30
25
45
85
89
81
86
83
78
75
72
74
72
65
71
73
69
52
4-MeOC6H4
4-NO2C6H4
3-CO2EtC6H4
3-CNC6H4
2-MeC6H4
2-CF3C6H4
2-Pyridine
3-Pyridine
2-Pyrazine
2-Thiophene
C6H5
7j
10j
7k
13a
13b
13c
13d
10k
16a
16b
16c
16d
4-MeOC6H4
4-NO2C6H4
3-Pyridine
a
Yields of isolated naphthyl 2-propynyl ethers.
Yields of isolated naphthofurans.
b

V. S. Prasada Rao Lingam et al. / Tetrahedron Letters 53 (2012) 5695–5698
5697
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CH2
Ar
O
Ar
CH2OH 6
2. Guével, R. L.; Oger, F.; Lecorgne, A.; Dudasova, Z.; Chevance, S.; Bondon, A.;
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DEAD, PPh3, THF
12
13a-d
CH2
CH2
O
C
HO
C
MW
Ar
Ar
7. Chandrashekhar, C. H.; Latha, K. P.; Vagdevi, H. M.; Vaidya, V. P. Der. Pharma
Chem. 2011, 3, 329.
CsF, DEA
8. Shashikala Devi, K.; Ramaiah, M.; Vanita, G. K.; Veena, K.; Vaidya, V. P. J. Chem.
Pharm. Res. 2011, 3, 445.
9. Son, J. K.; Jung, S. J.; Jung, J. H.; Fang, Z.; Lee, C. S.; Seo, C. S.; Moon, D. C.; Min, B.
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13. Mukhanova, T. I.; Lykova, O. A.; Alekseeva, L. M.; Granik, V. G. Chem. Heterocycl.
Compd. (N. Y.) 1998, 34, 651.
14
15
CH3
O
O
cyclization
(5-exo)
Ar
Ar
16a-d
17
14. Mudiganti, N. V. S.; Claessens, S.; Kimpe, N. D. Tetrahedron 2009, 65, 1716.
15. Liu, Z.; Liu, L.; Shafiq, Z.; Wu, Y.-C.; Wang, D.; Chen, Y.-J. Synthesis 2007, 1961,
13.
Scheme 3. Synthesis of naphtho[1,2-b]furans 16a–d.
16. Martín-Matute, B.; Nevado, C.; Cárdenas, D. J.; Echavarren, A. M. J. Am. Chem.
Soc. 2003, 125, 5757.
Having developed a general and reliable approach for the syn-
thesis of naphtho[2,1-b]furans 10, we explored the scope of this ap-
proach for the synthesis of isomeric naphtho[1,2-b]furan 16 as
shown in Scheme 3. Toward this end, we prepared the desired 1-
17. Maeyama, K.; Iwasawa, N. J. Org. Chem. 1999, 64, 1344.
18. Xu, X.; Liu, J.; Liang, L.; Li, H.; Li, Y. Adv. Synth. Catal. 2009, 351, 2599.
19. Kundu, D.; Samim, M.; Majee, A.; Hajra, A. Chem. Asian J. 2011, 6, 406.
20. Jana, R.; Paul, S.; Biswas, A.; Ray, J. K. Tetrahedron Lett. 2010, 51, 273.
21. Pan, C.; Yu, J.; Zhou, Y.; Wang, Z.; Zhou, M.-M. Synlett. 2006, 1657.
22. Liu, G.; Lu, X. Tetrahedron 2008, 64, 7324.
23. Black, M.; Cadogan, J. I. G.; McNab, H.; MacPherson, A. D.; Roddam, V. P.; Smith,
C.; Swenson, H. R. J. Chem. Soc., Perkin Trans. 1 1997, 2483.
24. Mayring, L.; Severin, T. Chemische Berichte 1981, 114, 3863.
25. Saidi, M. R. Heterocycles 1982, 19, 1473.
26. Duperrouzel, P.; Leep-Ruff, E. Can. J. Chem. 1980, 58, 51.
27. Lingam, V. S.; Ramanatham, V.; Mukkanti, K.; Thomas, A.; Balasubramanian, G.
Tetrahedron Lett. 2008, 49, 4260.
28. Some of the aryl propargyl alcohols used were purchased from commercial
sources and some were prepared. These intermediates can easily be prepared
in high yields by coupling aryl or heteroaryl iodides with propargyl alcohol
under Sonagashira reaction conditions using Cu(I) iodide and
naphthyl 2-propynyl ethers 13 by etherification of
a-naphthol 12
with functionalized propargyl alcohols 6 under Mitsunobu reaction
conditions. The desired ethers 13a–d35 were isolated in 91–96%
yield. The microwave-assisted rearrangement of these intermedi-
ates was studied and the results are given in Table 1 (entries 12–15).
It was observed that the rearrangement of 1-naphthyl 2-propy-
nyl ethers is less facile even under microwave-assisted reaction
conditions. Relatively lower yields were observed for 16a–d36
(52–73%) compared to the corresponding regioisomeric products
10a–c (81–89%), 10i (74%) under identical conditions. The reaction
time also increased in the naphtho[1,2-b]furan series compared to
the naphtho[2,1-b]furan series as shown in Table 1. This can be
attributed to the poor nucleophilicity of the b-carbon of naphthyl
ring which slows down the rearrangement of ether 13 to allenic
ketone 14 via a [3,3]-sigmatropic rearrangement. As in the previ-
ous series, the formation of the corresponding fused pyran deriva-
tive 17 (4-aryl-3H-benzo[h]chromene) was not observed in the
reaction.31,32
In summary, we have developed a novel and powerful synthetic
approach, which is equally effective for the synthesis of both of the
regioisomers of angularly-fused naphthofurans. The method devel-
oped has potential applications for assembling a variety of struc-
turally diverse functionalized naphthofurans from readily
available starting materials. The use of inexpensive starting mate-
rials, relatively short reaction time, a straightforward purification
process, and good yields of products are the main advantages of
the method. We believe that the method developed is a valuable
addition to the existing ones and is useful to practicing synthetic
chemists.
bis(triphenylphosphine)palladium(II)dichloride
[PdCl2(PPh3)2]
in
the
presence of excess triethylamine in N,N-dimethyl formamide.
29. Swamy Kumara, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; PavanKumar, K. V.
P. Chem. Rev. 2009, 109, 2551.
30. Synthesis of 2-[(3-phenylprop-2-yn-1-yl)oxy]naphthalene (7a): To
a stirred
solution of b-naphthol (500, mg, 3.468 mmol), 3-phenylprop-2-yn-1-ol
5
(458 mg, 3.468 mmol), and triphenylphosphane (1.09 g, 4.155 mmol) in
tetrahydrofuran (20 ml) under nitrogen atmosphere was added diethyl
azodicarboxylate (725 mg, 4.163 mmol) drop-wise and the mixture was
further stirred at room temperature for 6 h. The solvent was evaporated
under reduced pressure on a rotary evaporator to give a viscous residue. The
residue was purified by flash silica gel column chromatography using 4% EtOAc
in hexane to give 860 mg (96%) of 7a as an off-white solid; mp 95–96 °C; IR
(KBr) 3045, 2230, 1625, 1596, 1466, 1379, 1256, 1214, 1181, 1118 cmÀ1 1H
;
NMR (300 MHz, CDCl3): d 5.03 (s, 2H), 7.22–7.38 (m, 6H), 7.43–7.46 (m, 3H),
7.76–7.79 (m, 3H); 13C NMR (75 MHz, CDCl3): d 56.6, 83.7, 87.3, 107.4, 118.8,
122.2, 123.9, 126.4 (2C), 126.9, 127.6, 128.2, 128.6, 129.2, 129.4, 131.8 (2C),
134.3, 155.6; MS (APCI): m/z (%) 259 [MH+, 100].
31. (a) Ishii, H.; Ishikawa, T.; Takeda, S.; Ueki, S.; Suzuki, M.; Harayama, T. Chem.
Pharm. Bull. 1990, 38, 1775; (b) Ishii, H.; Ishikawa, T.; Takeda, S.; Ueki, S.;
Suzuki, M. Chem. Pharm. Bull. 1992, 40, 1148.
32. Iwai, I.; Ide, J. Chem. Pharm. Bull. 1962, 10, 926.
33. (a) Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J. J. Org. Chem. 2005, 70,
4414; (b) Lin, Y.-L.; Cheng, J.-Y.; Chu, Y.-H. Tetrahedron 2007, 63, 10949.
34. Synthesis of 2-methyl-1-phenylnaphtho[2,1-b]furan (10a): a solution of 2-[(3-
phenylprop-2-yn-1-yl)oxy]naphthalene 7a (300 mg, 1.161 mmol) and cesium
fluoride (265 mg, 1.744 mmol) in N,N-diethylaniline (2 ml) in a pressurized
reaction vial was irradiated in a 200 W microwave reactor at 150 °C for 20 min.
The dark brown mixture was poured into ice-cold water (50 ml) and extracted
with EtOAc (2 Â 50 ml). The combined organic layers were successively
washed with 2N HCl (2 Â 50 ml), water, (2 Â 50 ml) and brine (25 ml). The
residue obtained after evaporation of the solvent was purified by flash silica gel
column chromatography using 5% EtOAc in hexane as eluent to give 255 mg
(85%) of the product as an off-white solid; mp 60–61 °C; IR (KBr) 2920, 1623,
Acknowledgments
We thank Dr. Rajesh Dwivedi and his team for analytical sup-
port of this work. We also thank Ms. Rajni Thakur for technical sup-
port and for checking reproducibility of
reported in this Letter.
a few experiments
1578, 1495, 1442, 1395, 1271, 1214, 1006 cmÀ1 1H NMR (300 MHz, DMSO-d6:
;
d 2.39 (s, 3H), 7.33 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.51–7.58 (m, 5H),
7.67 (d, J = 8.4 Hz, 1H), 7.73–7.80 (m, 2H), 8.01 (d, J = 7.8 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6): d 12.2, 112.3, 118.5, 121.6, 122.4, 124.3, 124.9, 126.0,
127.3, 128.0, 129.0 (2C), 129.1, 130.3 (2C), 130.6, 133.5, 150.8, 151.3; MS
(APCI): m/z (%) 259 [MH+, 100]; Anal. Calcd for C19H14O: C, 88.34; H, 5.46%.
Found: C, 88.30; H, 5.48%.
References and notes
1. (a) Venkata Sastry, M. N.; Claessens, S.; Habonimana, P.; Kimpe, N. D. J. Org.
Chem. 2010, 75, 2274; (b) Lumb, J.-P.; Choong, K. C.; Trauner, D. J. Am. Chem. Soc.
2008, 130, 9230; (c) Ho, L.-K.; Don, M.-J.; Chen, H.-C.; Yeh, S.-F.; Chen, J.-M. J.
Nat. Prod. 1996, 59, 330; (d) Srivastava, V.; Negi, A. S.; Kumar, J. K.; Faridi, U.;
35. Synthesis
of
3-[3-(naphthalene-1-yloxy)prop-1-yn-1-yl]pyridine
(13d):
Mitsunobu reaction of
a-naphthol 12 (500 mg, 3.468 mmol) with 3-(pyridin-

5698
3-yl)prop-2-yn-1-ol
V. S. Prasada Rao Lingam et al. / Tetrahedron Letters 53 (2012) 5695–5698
(462 mg,
3.468 mmol)
in
the
presence
of
1.734 mmol) in DEA (2 ml) as described above for 45 min. followed by flash
silica gel column chromatography using 20% EtOAc in petroleum ether gave
156 mg (52%) of the product as off-white crystals; mp 78–79 °C; IR (KBr): 3056,
triphenylphosphane (1.09 mg, 4.155 mmol) and DEAD (725 mg, 4.163 mmol)
as described above gave 818 mg (91%) of the product as a colorless oil; IR
(neat): 3054, 2240, 1580, 1404, 1272, 1218, 1097 1021 cmÀ1
;
1H NMR
1562, 1478, 1413, 1380, 1275, 1217, 1175, 1086, 1009 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 5.13 (s, 2H), 7.02 (d, J = 7.2 Hz, 1H), 7.20–7.26 (m, 1H),
7.40 (t, J = 7.8 Hz, 1H), 7.45–7.52 (m, 3H), 7.71 (d, J = 7.8 Hz, 1H), 7.79–7.85 (m,
1H), 8.28–8.34 (m, 1H), 8.53 (d, J = 4.5 Hz, 1H), 8.68 (s, 1H); 13C NMR (75 MHz,
CDCl3): d 56.7, 83.8, 87.4, 105.6, 119.4, 121.2, 121.9, 122.8, 125.3, 125.5, 125.6,
126.4, 127.4, 134.5, 138.6, 148.9, 152.3, 153.4; MS (APCI): m/z (%) = 260 [MH+,
100].
(300 MHz, CDCl3): d 2.66 (s, 3H), 7.40–7.52 (m, 2H), 7.54–7.62 (m, 2H), 7.68
(d, J = 8.4 Hz, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 8.31 (d,
J = 7.8 Hz, 1H), 8.63 (d, J = 4.2 Hz, 1H), 8.82 (s, 1H); 13C NMR (75 MHz, CDCl3): d
12.8, 114.9, 117.6, 119.7, 121.0, 123.4, 123.5, 123.6, 124.9, 126.3, 128.3, 129.0,
131.1, 136.0, 148.1, 149.3, 149.8, 151.1; MS (ESI): m/z (%) = 260 [MH+, 100];
Anal. Calcd for C18H13NO: C, 83.37; H, 5.05; N, 5.40%. Found: C, 83.35; H, 5.07;
N, 5.36%.
36. Synthesis of 3-(2-methylnaphtho[1,2-b]furan-3-yl)pyridine (16d): microwave
irradiation of 13d (300 mg, 1.156 mmol) in the presence of CsF (263 mg,